CD8+ T cells play an important role in most transplantation reactions involving either MHC class I or multiple minor histocompatibility antigen (miHA) disparities. The CD8 molecule functions as a coreceptor for the T cell receptor (TCR) recognition of peptide antigens presented by MHC class I molecules on an appropriate antigen presenting cell. We have recently used a synthetic peptide analog mapping approach to study the structure/function relationship of the surfaces of CD8, and have unveiled sites potentially involved in class I MHC binding. Synthetic peptide mimics of these interactive sites appear to have inhibitory activity on the activation and effector function of CD8+ cytotoxic T lymphocytes (CTL) and therefore have potential as new immunoregulatory agents in allogeneic transplantation settings. In this regard, we will investigate the efficacy and mechanism of action of these CD8 inhibitors in two transplantation modalities - skin allograft rejection and graft-versus-host disease (GVHD). Skin allografts are recognized as a representative model for the classic rejection processes that occur in several types of solid organ transplantation. GVHD is a major, and often lethal, complication of clinical allogeneic bone marrow transplantation (BMT). The risk of GVHD can be reduced by HLA-matching of the marrow donor and recipient, with a matched sibling being the primary choice. However, even in this case GVHD is still prevalent (50-60 percent incidence), particularly due to disparities in minor histocompatibility antigens (miHA), which are capable of generating strong CD8+ T cell responses. In this proposal our specific aims are to: (1) determine the efficacy of inhibitors designed from the CDR2 and DE-loop surfaces of the CD8alpha molecule in the skin allograft and GVHD preclinical models; (2) determine the mechanism of action of the CD8 inhibitors; and (3) evaluate the immunocompetent status of BMT recipients in the GVHD models after treatment with the inhibitory agents.